Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort.

CACNA1I is implicated in the susceptibility to schizophrenia by large-scale genetic association studies of single nucleotide polymorphisms. However, the channelopathy of CACNA1I in schizophrenia is unknown. CACNA1I encodes CaV3.3, a neuronal voltage-gated calcium channel that underlies a subtype of T-type current that is important for neuronal excitability in the thalamic reticular nucleus and other regions of the brain. Here, we present an extensive functional characterization of 57 naturally occurring rare and common missense variants of CACNA1I derived from a Swedish schizophrenia cohort of more than 10 000 individuals. Our analysis of this allelic series of coding CACNA1I variants revealed that reduced CaV3.3 channel current density was the dominant phenotype associated with rare CACNA1I coding alleles derived from control subjects, whereas rare CACNA1I alleles from schizophrenia patients encoded CaV3.3 channels with altered responses to voltages. CACNA1I variants associated with altered current density primarily impact the ionic channel pore and those associated with altered responses to voltage impact the voltage-sensing domain. CaV3.3 variants associated with altered voltage dependence of the CaV3.3 channel and those associated with peak current density deficits were significantly segregated across affected and unaffected groups (Fisher's exact test, P = 0.034). Our results, together with recent data from the SCHEMA (Schizophrenia Exome Sequencing Meta-Analysis) cohort, suggest that reduced CaV3.3 function may protect against schizophrenia risk in rare cases. We subsequently modelled the effect of the biophysical properties of CaV3.3 channel variants on thalamic reticular nucleus excitability and found that compared with common variants, ultrarare CaV3.3-coding variants derived from control subjects significantly decreased thalamic reticular nucleus excitability (P = 0.011). When all rare variants were analysed, there was a non-significant trend between variants that reduced thalamic reticular nucleus excitability and variants that either had no effect or increased thalamic reticular nucleus excitability across disease status. Taken together, the results of our functional analysis of an allelic series of >50 CACNA1I variants in a schizophrenia cohort reveal that loss of function of CaV3.3 is a molecular phenotype associated with reduced disease risk burden, and our approach may serve as a template strategy for channelopathies in polygenic disorders.

Perceptual enhancement and suppression correlate with V1 neural activity during active sensing.

Perception in multiple sensory modalities is an active process that involves exploratory behaviors. In humans and other primates, vision results from sensory sampling guided by saccadic eye movements. Saccades are known to modulate visual perception, and a corollary discharge signal associated with saccades appears to establish a sense of visual stability. Neural recordings have shown that saccades also modulate activity widely across the brain. To investigate the neural basis of saccadic effects on perception, simultaneous recordings from multiple neurons in area V1 were made as animals performed a contrast detection task. Perceptual and neural measures were compared when the animal made real saccades that brought a stimulus into V1 receptive fields and when simulated saccades were made (identical retinal stimulation but no eye movement). When real saccades were made and low spatial frequency stimuli were presented, we observed a reduction in both perceptual sensitivity and neural activity compared with simulated saccades; conversely, with higher spatial frequency stimuli, saccades increased visual sensitivity and neural activity. The performance of neural decoders, which used the activity of the population of simultaneously recorded neurons, showed saccade effects on sensitivity that mirrored the frequency-dependent perceptual changes, suggesting that the V1 population activity could support the perceptual effects. A minority of V1 neurons had significant choice probabilities, and the saccades decreased both average choice probability and pairwise noise correlations. Taken together, the findings suggest that a signal related to saccadic eye movements alters V1 spiking to increase the independence of spiking neurons and bias the system toward processing higher spatial frequencies, presumably to enhance object recognition. The effects of saccades on visual perception and noise correlations appear to parallel effects observed in other sensory modalities, suggesting a general principle of active sensory processing.

A Study on the Efficacy of a Naloxone Training Program.

INTRODUCTION: The use of naloxone to reverse a potentially fatal opioid overdose is a harm reduction strategy that reduces mortality and increases the potential for referral to substance use treatment for affected individuals. In the setting of outreach performed by a street medicine team, we aimed to determine the effectiveness of an educational intervention involving distribution of naloxone accompanied by a brief instructive session about opioids, opioid overdose, and medication administration. METHODS: Our street medicine outreach team distributed 200 naloxone kits to clinicians and volunteers involved in caring for patients on 'street rounds,' as well as in shelters, soup kitchens, and street medicine clinic settings. Those receiving a naloxone kit engaged in a peer-reviewed presentation on how to safely use the medication to reverse a potentially fatal opioid overdose. The study team developed and administered a pre- and post-survey of 10 multiple choice questions on material covered in the educational training. The pre- and post-survey scores were compared to assess the effectiveness of implementing this training. Results were stratified by participant gender and age group. RESULTS: Out of the 200 participants, six were excluded from the analysis due to completely missing data from one or both surveys. The mean age of participants was 40.2±12.5 years; 120 (65.6%) were female, 62 (33.9%) were male, and 1 (0.6%) identified as nonbinary. Every survey question had an increase in correct responses from pre-survey to post-survey (identified by an increase in the percentage of correct responses). The mean survey total score increased from 5.5±1.6 to 7.5±1.3. Within the sample of 194, the mean difference in scores from pre-survey to post-survey was 2.02 points (95% CI [1.77, 2.26]), p<0.0001. Males had a mean increase in the total score from 5.6±1.8 to 7.4±1.1. Females had a mean increase in the total score from 5.5±1.5 to 7.5±1.3. The difference in total scores in males was 1.89 points (95% CI [1.42, 2.35]), p<0.0001, and in females was 2.02 points (95% CI [1.71, 2.32]), p<0.0001. Post-test scores improved in all age groups. CONCLUSION: The educational training on opioids, opioid overdose, and the use of naloxone was an effective adjunct to naloxone kit distribution to volunteers and clinicians caring for people experiencing homelessness.

Testing a computational model of causative overgeneralizations: Child judgment and production data from English, Hebrew, Hindi, Japanese and K'iche'.

How do language learners avoid the production of verb argument structure overgeneralization errors ( *The clown laughed the man c.f. The clown made the man laugh), while retaining the ability to apply such generalizations productively when appropriate? This question has long been seen as one that is both particularly central to acquisition research and particularly challenging. Focussing on causative overgeneralization errors of this type, a previous study reported a computational model that learns, on the basis of corpus data and human-derived verb-semantic-feature ratings, to predict adults' by-verb preferences for less- versus more-transparent causative forms (e.g., * The clown laughed the man vs The clown made the man laugh) across English, Hebrew, Hindi, Japanese and K'iche Mayan. Here, we tested the ability of this model (and an expanded version with multiple hidden layers) to explain binary grammaticality judgment data from children aged 4;0-5;0, and elicited-production data from children aged 4;0-5;0 and 5;6-6;6 ( N=48 per language). In general, the model successfully simulated both children's judgment and production data, with correlations of r=0.5-0.6 and r=0.75-0.85, respectively, and also generalized to unseen verbs. Importantly, learners of all five languages showed some evidence of making the types of overgeneralization errors - in both judgments and production - previously observed in naturalistic studies of English (e.g., *I'm dancing it). Together with previous findings, the present study demonstrates that a simple learning model can explain (a) adults' continuous judgment data, (b) children's binary judgment data and (c) children's production data (with no training of these datasets), and therefore constitutes a plausible mechanistic account of the acquisition of verbs' argument structure restrictions.

Kirschner wire prepared pilot holes improve screw pullout strength in synthetic osteoporotic-type bone.

OBJECTIVES: To compare the pullout strength and maximal insertional torque of pilot holes prepared with the traditional twist drill bit versus a smooth Kirschner wire. METHODS: Pilot holes were prepared using a drill press with either a 2.5 mm twist drill bit or a 2.5 mm smooth Kirschner wire into 2 distinct polyurethane foam densities representing severe and mild osteoporotic bone. 3.5 mm cortical and 4.0 mm cancellous screws were then inserted freehand into the prepared holes. All permutations of pilot hole type, screw size and foam density were tested for maximum pullout strength and maximum insertional torque. RESULTS: Kirschner wire prepared pilot holes resulted in significantly higher pullout load than drill bit holes in low density blocks (P < 0.001), but not in high density blocks (P = 0.232). There was no statistical difference (P > 0.05) for maximum insertional torque in the pilot hole preparation type. CONCLUSION: In severely osteoporotic bone, Kirschner wire pilot hole preparation may improve screw pullout strength.

The crosslinguistic acquisition of sentence structure: Computational modeling and grammaticality judgments from adult and child speakers of English, Japanese, Hindi, Hebrew and K'iche'.

This preregistered study tested three theoretical proposals for how children form productive yet restricted linguistic generalizations, avoiding errors such as *The clown laughed the man, across three age groups (5-6 years, 9-10 years, adults) and five languages (English, Japanese, Hindi, Hebrew and K'iche'). Participants rated, on a five-point scale, correct and ungrammatical sentences describing events of causation (e.g., *Someone laughed the man; Someone made the man laugh; Someone broke the truck; ?Someone made the truck break). The verb-semantics hypothesis predicts that, for all languages, by-verb differences in acceptability ratings will be predicted by the extent to which the causing and caused event (e.g., amusing and laughing) merge conceptually into a single event (as rated by separate groups of adult participants). The entrenchment and preemption hypotheses predict, for all languages, that by-verb differences in acceptability ratings will be predicted by, respectively, the verb's relative overall frequency, and frequency in nearly-synonymous constructions (e.g., X made Y laugh for *Someone laughed the man). Analysis using mixed effects models revealed that entrenchment/preemption effects (which could not be distinguished due to collinearity) were observed for all age groups and all languages except K'iche', which suffered from a thin corpus and showed only preemption sporadically. All languages showed effects of event-merge semantics, except K'iche' which showed only effects of supplementary semantic predictors. We end by presenting a computational model which successfully simulates this pattern of results in a single discriminative-learning mechanism, achieving by-verb correlations of around r = 0.75 with human judgment data.

Transsacadic Information and Corollary Discharge in Local Field Potentials of Macaque V1.

Approximately three times per second, human visual perception is interrupted by a saccadic eye movement. In addition to taking the eyes to a new location, several lines of evidence suggest that the saccades play multiple roles in visual perception. Indeed, it may be crucial that visual processing is informed about movements of the eyes in order to analyze visual input distinctly and efficiently on each fixation and preserve stable visual perception of the world across saccades. A variety of studies has demonstrated that activity in multiple brain areas is modulated by saccades. The hypothesis tested here is that these signals carry significant information that could be used in visual processing. To test this hypothesis, local field potentials (LFPs) were simultaneously recorded from multiple electrodes in macaque primary visual cortex (V1); support vector machines (SVMs) were used to classify the peri-saccadic LFPs. We find that LFPs in area V1 carry information that can be used to distinguish neural activity associated with fixations from saccades, precisely estimate the onset time of fixations, and reliably infer the directions of saccades. This information may be used by the brain in processes including visual stability, saccadic suppression, receptive field (RF) remapping, fixation amplification, and trans-saccadic visual perception.

Industrial-age doubling of snow accumulation in the Alaska Range linked to tropical ocean warming.

Future precipitation changes in a warming climate depend regionally upon the response of natural climate modes to anthropogenic forcing. North Pacific hydroclimate is dominated by the Aleutian Low, a semi-permanent wintertime feature characterized by frequent low-pressure conditions that is influenced by tropical Pacific Ocean temperatures through the Pacific-North American (PNA) teleconnection pattern. Instrumental records show a recent increase in coastal Alaskan precipitation and Aleutian Low intensification, but are of insufficient length to accurately assess low frequency trends and forcing mechanisms. Here we present a 1200-year seasonally- to annually-resolved ice core record of snow accumulation from Mt. Hunter in the Alaska Range developed using annual layer counting and four ice-flow thinning models. Under a wide range of glacier flow conditions and layer counting uncertainty, our record shows a doubling of precipitation since ~1840 CE, with recent values exceeding the variability observed over the past millennium. The precipitation increase is nearly synchronous with the warming of western tropical Pacific and Indian Ocean sea surface temperatures. While regional 20th Century warming may account for a portion of the observed precipitation increase on Mt. Hunter, the magnitude and seasonality of the precipitation change indicate a long-term strengthening of the Aleutian Low.